Chronic Obstructive Pulmonary Disease (COPD), a group of disorders characterized by limitations in airflow, affects over 14 million Americans and is the fourth leading cause of death in the United States. COPD is also a major cause of disability and was the primary cause of 726,000 hospitalizations and 1.5 million emergency room visits in 2000. Current treatment and detection strategies have made little impact on the disease's mortality and morbidity. These observations prompted the National Heart, Lung, and Blood Institute to organize a Working Group, "Clinical Research in COPD: Needs and Opportunities." This Working Group recommended characterizing the development and progression of COPD with measures and biomarkers related to current concepts of pathogenesis, anticipating that these biomarkers could be used in the discovery and development of drugs and therapies for COPD. In view of these recommendations, we propose to obtain fundamentally new, detailed information about localized changes in the structure of emphysematous lungs and the physiology of gas exchange by employing 3He MRI to assess COPD patients and subjects at risk for developing COPD. We recently implemented a novel method for measuring the regional partial pressure of oxygen and furthered the development of a method for evaluating emphysema using the measurement of the apparent diffusion coefficient of 3He. The central hypothesis of this proposal is that quantitative assessments derived from MR imaging can detect early alterations in structure and function that precede clinically apparent COPD and predict progression of disease earlier and better than established clinical methods. The successful completion of this research will lead to significant improvements in the understanding of COPD and to faster, more economical methods for characterizing disease response to therapy. Our research has four specific aims. The first is to further develop the techniques for MR imaging of 3He so that it becomes a more robust modality which is better suited for research and clinical use. The second aim is to determine the reproducibility of structural and functional assessments in healthy non-smokers, asymptomatic smokers, and COPD patients. The third aim is to determine which of these assessments can best predict the decline in lung performance which may lead to the development of COPD. The final specific aim is to measure variations in the imaging and clinical assessments over the course of the study and correlations among the rates of change of the different assessments. PUBLIC HEALTH RELEVANCE MR biomarkers, alone or in combination with conventional pulmonary function tests, can: A) distinguish among different forms of COPD, B) detect early alterations in structure and function which are precursors to clinically apparent COPD, and C) detect progression of disease earlier than established clinical methods. These novel markers will significantly improve understanding of COPD and will be critical to characterizing disease response to therapy.